Methods of treating tardive dyskinesia and other movement disorders

ABSTRACT

The present invention describes a novel treatment for movement disorders, including tardive dyskinesia, tic disorders, Tourette&#39;s syndrome, and blepharospasm, and other focal dystonias. The treatment of the present invention utilizes agents that simultaneously act as NMDA-type glutamate receptor antagonists and GABA-A receptor agonists. Preferably these two activities are characteristic of a single agent, for example acamprosate. Alternatively, separate agents having these activities can be combined and administered together. The invention also provides a third agent that acts as a non-competitive NMDA-receptor blocking agent or ion channel blocker that augments the effect of the primary treatment. A particularly preferred ion channel blocking agent is magnesium. Alternatively, magnesium can be administered alone for prevention and treatment of movement disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of and claims priority toco-pending U.S. application Ser. No. 09/893,244, filed on Jun. 27, 2001,entitled METHODS OF TREATING TARDIVE DYSKINESIA AND OTHER MOVEMENTDISORDERS, which is a divisional of U.S. application Ser. No.09/193,892, filed Nov. 18, 1998, now U.S. Pat. No. 6,294,583, which is acontinuation-in-part of U.S. application Ser. No. 09/006,641, filed Jan.13, 1998, now U.S. Pat. No. 5,952,389, the entire contents of each ofwhich are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Movement disorders affect a significant portion of the population,causing disability as well as distress. This invention concerns thetreatment of several movement disorders: 1) tics, including multipletics and Gilles de la Tourette syndrome (TS); 2) tardive dyskinesia (TD)and related movement disorders induced by exposure to neuroleptic(antipsychotic) drugs; and 3) focal dystonias, including blepharospasmMeige syndrome, torticollis, spasmodic dysphonia, and writer's cramp.

2. Description of the Related Art

Tics are estimated to affect 1% to 13% of boys and 1% to 11% of girls,the male-female ratio being less than 2 to 1. Approximately 5% ofchildren between the ages of 7 and 11 years are affected with ticbehavior (Leckman et al., Neuropsychiatry of the Bas. Gang, December,20(4): 839-861, 1997). The estimated prevalence of multiple tics withvocalization, i.e. Tourette's syndrome, varies among different reports,ranging from 5 per 10,000 to 5 per 1,000. Tourette's syndrome is 3-4times more common in boys than girls and 10 times more common inchildren and adolescents than in adults (Leckman et al., supra; Esper etal, Tenn. Med., January, 90:18-20, 1997).

Tardive dyskinesia (TD) affects approximately 15-20% of patients treatedwith neuroleptic drugs (Khot et al., Neuroleptics and Classic TardiveDyskinesia, in Lang A E, Weiner W J (eds.): Drug Induced MovementDisorders, Futura Publishing Co., 1992, pp 121-166). Therefore, thecondition affects hundreds of thousands of people in the United Statesalone. The cumulative incidence of TD is substantially higher in women,in older people, and in those being treated with neuroleptics forconditions other than schizophrenia, such as bipolar disorder(manic-depressive illness) (see, e.g., Hayashi et al., Clin.Neuropharmacol, 19:390, 1996; Jeste et al., Arch. Gen. Psychiatry,52:756, 1995). Unlike the of the acute motor side effects of neurolepticdrugs, TD does not respond in general to antiparkinson drugs (Decker etal., New Eng. J. Med., October 7, p. 861, 1971).

Focal dystonias are a class of related movement disorders involving theintermittent sustained contraction of a group of muscles. The mostcommon is spasmodic torticollis, which involves twisting of the neck.Other examples are blepharospasm, which involves involuntary eyeclosure, and writer's cramp, which involves contraction of the musclesof the hand. The prevalence of focal dystonias in one US county wasestimated as 287 per million (Monroe County Study); this suggests thatat least 70,000 people are affected in the US alone.

Tardive dyskinesia (TD) is a chronic disorder of the nervous system,characterized by involuntary, irregular rhythmic movements of the mouth,tongue, and facial muscles. The upper extremities also may be involved.These movements may be accompanied, to a variable extent, by otherinvoluntary movements and movement disorders. These include rocking,writhing, or twisting movements of the trunk (tardive dystonia),forcible eye closure (tardive blepharospasm), an irresistible impulse tomove continually (tardive akathisia), jerking movements of the neck(tardive spasmodic torticollis), and disrupted respiratory movements(respiratory dyskinesia). The vast majority of TD cases are caused bythe prolonged use of antipsychotic drugs (neuroleptics). A relativelysmall number are caused by the use of other medications, such asmetoclopramide, that, like neuroleptics, block dopamine receptors. TDoften manifests or worsens in severity after neuroleptic drug therapy isdiscontinued. Resumption of neuroleptic therapy will temporarilysuppress the involuntary movements, but may aggravate them in the longrun.

TD is also associated with a variable degree of cognitive impairment.Cognitive dysfunction associated with TD may involve attention,concentration, memory, or executive functions such as judgment orabstract reasoning. (see, e.g., Sachdev et al., Acta Psychiatr Scand93:451, 1996; Waddington & Youssef, Psychol. Med. 26:681, 1996; Swartz,Neuropsychobiology 32:115, 1995). The cognitive impairment associatedwith TD usually is seen as a marker of underlying differences in brainfunction that predispose the patient to TD. However, it may also be dueto the TD itself, and may be either irreversible, or partiallyreversible if the TD is successfully treated.

The pathophysiology of TD has not been established definitively. It iswell known that blockade of dopamine receptors will lead to an increasednumber of dopamine receptors, and therefore to an increased sensitivityto dopamine of striatal neurons. (see, e.g. Andrews, Can J Psych 39:576,1994; Casey, in Psychopharmacology: The Fourth Generation of Progress,Raven Press, 1995). The first major hypothesis about the pathophysiologyof TD was that TD was the result of this hypersensitivity of striatalneurons to dopamine. In support of the “dopamine supersensitivity”hypothesis, it is noted that dopamine agonists can aggravate thedisorder (Bezchibnyk-Butler & Remington, Can J. Psych., 39:74, 1994).However, the dopamine supersensitivity hypothesis is not compatible withthe observation that TD and Parkinsonism (a dopamine deficiency state)infrequently exist together in the same patient.

Other studies have suggested that irreversible cases of TD may berelated to excitotoxic damage to the basal ganglia (Andreassen &Jorgensen, Pharmacol. Biochem. Behav., 49(2):309-312, 1994; Tsai etal.,: Am J Psych, September 155:9, 1207-13, 1998). An acquireddeficiency of the inhibitory neurotransmitter GABA has also beenimplicated in the development of TD (Delfs et al. Experimental Neurol.,133:175-188, 1995).

A widely-studied animal mode of TD, that of vacuous chewing movements(VCM) in rats, has also yielded evidence for a glutamate-basedexcitotoxic mechanism in the development of the disorder (Meshul et al;Psychopharmacology (Berl), 125:238-47, 1996 June; Andreassen et al; Br JPharmacol, 199:751-7, 1996 October) When administered to rats with VCM,ethanol acutely decreases the animals' orofacial movements. This effectis prevented if the rats are pre-treated with a benzodiazepine inverseagonist, suggesting that it is mediated by stimulation of GABA-Areceptors by ethanol (Stoessl, Pharmacol. Biochem. Behav. July,54:541-6, 1996 July) Stoessl suggests that “GABAergic stimulation”deserves further investigation in the treatment of TD. He does not,however, advance the idea of treating TD with combined GABA agonism andNMDA antagonism, nor suggest using acamprosate as a treatment for TD.

The physical manifestations of TD can resemble movement disordersassociated with degenerative diseases such as Huntington's disease andParkinson's disease. Patients with TD can show chorea (quick, irregularmovements of the extremities) indistinguishable from that seen in casesof Huntington's disease. Neck, trunk and limb movements of TD can beindistinguishable from those of the “peak-dose dyskinesia” associatedwith prolonged treatment of Parkinson's disease with levodopa.

Recent research suggests that Vitamin E can reduce symptoms of TDmodestly (Lohr & Caliguiri, J Clin Psychiatry 57;167, 1996; Dabiri etal. Am. J. Psychiatry, June, 151(6):925-926, 1994). GABA agonists suchas baclofen and various benzodiazepines have also been the subject ofsome positive reports and are widely used in practice to ameliorate thesymptoms of TD, probably because their low toxicity justifies their usedespite their limited efficacy. (Gardos & Cole, Psychopharmacology: TheFourth Generation of Progress, eds. Bloom and Kupfer, pp. 1503-1510,1995). This review only cited reports of variable benefits associatedwith other agents including propranolol, clonidine, cholinergicagonists, buspirone and calcium-channel antagonists. However, none ofthese has become a generally accepted treatment for either the movementor cognitive disorders associated with TD.

In U.S. Pat. No. 5,602,150, by Lidsky et al., it was proposed thatco-administration of taurine or taurine derivatives together withneuroleptics, might prevent the emergence of tardive movement disorders,on the theory that the latter are due to excitotoxic damage againstwhich taurine would protect. The recommendation of taurine is based onstudies in a single animal model. The experiments reported do not dealwith any therapeutic effects of taurine on established movements, eitherin the presence of continued neuroleptic therapy or otherwise. Neitherthe patent nor the experiments cited in it predict or imply that taurineor derivatives will be beneficial for established movement disorders.Moreover, the mechanism proposed by Lidsky et al., (supra) is based onlong-term neuroprotection. He neither asserts, infers, or suggests thattaurine or derivatives might have any immediate, short term effect onmovement disorders.

In co-pending, commonly-owned applications Ser. Nos. 08/861,801 and09/006,641, incorporated herein by reference, treatments with memantine(a congener of amantadine and a N-methyl-D-aspartate type (NMDA)receptor blocker as well as a dopamine agonist), and acamprosate (acalcium salt of a derivative of the amino acid taurine and a NMDA-typereceptor blocker as well as a agonist), were advanced as effectivetreatments for both the movement and cognitive disorders associated withTD, and were reported to be dramatically effective in several severelyaffected individuals.

A tic is an abrupt repetitive movement, gesture, or utterance that oftenmimics a normal type of behavior. Motor tics include movements such aseye blinking, head jerks or shoulder shrugs, but can vary to morecomplex purposive appearing behaviors such as facial expressions ofemotion or meaningful gestures of the arms and head. In extreme cases,the movement can be obscene (copropraxia) or self injurious. Phonic orvocal tics range from throat clearing sounds to complex vocalizationsand speech, sometimes with coprolalia (obscene speech) (Leckman et al.,supra). Tics are irregular in time, though consistent regarding themuscle groups involved. Characteristically, they can be suppressed for ashort time by voluntary effort.

Gilles de la Tourette syndrome (TS) is the most severe tic disorder.Patients with TS have multiple tics, including at least one vocal(phonic) tic. TS becomes apparent in early childhood with thepresentation of simple motor tics, for example, eye blinking or headjerks. Initially, tics may come and go, but in time tics becomepersistent and severe and begin to have adverse effects on the child andthe child's family. Phonic tics present, on average, 1 to 2 years afterthe onset of motor tics. By the age of 10, most children have developedan awareness of the premonitory urges that frequently precede a tic.Such premonitions may enable the individual to voluntary suppress thetic, yet premonition unfortunately adds to the discomfort associatedwith having the disorder. By late adolescence/early adulthood ticdisorders can improve significantly in certain individuals. However,adults who continue to suffer from tics often have particularly severeand debilitating symptoms. (Leckman et al., supra).

The pathophysiology of tic disorders like, that of TD, has not yet beenestablished, although several plausible hypotheses have been set forth.Excessive activity of a cortical-striatal-pallidal-thalamic-corticalsensorimotor loop has been implicated in the lack of motor impulsecontrol associated with tic disorders (Ziemann et al., Am. J.Psychiatry, Vol 154, September, 1997; Leckman et al., supra). Thishyperactivity may reflect excessive dopaminergic activity in thestriatum, or a relative deficiency of inhibitory transmission. Whiledysfunction of the basal ganglia or their connections is likely to bepresent, the basal ganglia, thalamus, and motor cortex are anatomicallynormal in most cases.

Patients with moderate to severe motor and vocal tics are likely torequire drug therapy. Many classes of neurological and psychiatricmedications have been tried, but only neuroleptics, alpha-2 adrenergicagonists, and clonazepam have attained the status of standardtreatments. (For recent reviews see Chappell et al., Neur. Clin. ofNorth Am., 15(2), May 1997; Kurlan, Neurol. Clin., May, 15:403-409,1997; Lichter et al., J. Child Neur., 11(2), March, 1996; Leckman etal., supra; Esper et al, Tenn. Med., January, 90:18-20, 1997; Scahill etal., J. Child Adolesc Phychopharcmacol, 7(2), 1997; incorporated hereinby reference). Unfortunately, all three of the commonly-used treatmentfor TS have significant drawbacks.

The most common therapies used for the treatment of tic disorders arethe neuroleptics (i.e. dopamine antagonist antipsychotic drugs). Withinthis category, haloperidol and pimozide are most often used in theUnited States. Neuroleptic treatment usually will suppress theinvoluntary movements of tic disorders, with up to 85% of patientsexperiencing relief—(Esper et al., supra). The side effects ofneuroleptic drugs include sedation, depression, parkinsonism, cognitiveimpairment, and tardive dyskinesia. Other tardive movement disorders candevelop with prolonged use. The intolerability of side effects oftenleads patients to discontinue neuroleptic therapy for TS, while the riskof TD makes most physicians unwilling to use them in milder cases. Thosewith more severe TS must often make an unpleasant choice betweendistressing symptoms and distressing side effects. People with simpletics may experience emotional distress, embarrassment, impairedself-esteem, or physical injury if their tics are sufficiently violent.Yet, they usually will not be treated with neuroleptics because theirside effects and long-term toxicity that are not acceptable in thetreatment of relatively mild cases.

Other drug treatments for TS do not carry the risk of TD. But they areless efficacious than neuroleptics. The most common non-neurolepticalternatives are alpha-2 adrenergic agonists such as clonidine.Unfortunately, fewer than 50% (perhaps as few as 25%) of patientstreated with clonidine show clinically significant improvement oftic-related symptoms (Esper et al., supra; Chappell et al., supra).Further, many patients whose tics do respond to clonidine will have sideeffects that limit its use, most often hypotension or sedation.

Another non-neuroleptic treatment, clonazepam, a benzodiazepine withGABA-A and serotonergic actions, has some efficacy in the treatment ofTourette's syndrome (Steingard et al., J. Am Acad Child AdolescPsychiatry, March-April, 33:394-9, 1994). Sedation and ataxia limit thedosage of clonazepam; the tolerable dose often is below that needed tosuppress the patient's tics.

A new class of compounds that act as antagonists of brain serotonergic5-HT₂ receptors initially showed promising results, although childrenand adolescents experience increase in sensitivity to side effects.(Chappell et al., supra). Additional alternatives that have receivedrecent attention include antioxidant treatment (Rotrosen et al., Prost.Leuk. and Ess. Fatty Acids, 55(1 & 2), 1996), transcranial magneticstimulation (Ziemann et al., supra), nicotine treatment (Sanberg et al.,Pharmacol. Ther., 74(1)., 1997; Silver et al., J. Am. Acad. Adolesc.Psychiatry, Vol 35, December, 1996) and botulinum toxin treatment (Esperet al., supra). While each of these treatments has offered clinicallysignificant relief to individual patients, none has replacedneuroleptics as the treatment of choice. Clearly, there is a need foradditional treatments for tics and TS that do not carry the side effectsand long term risks of neuroleptics.

It has been suggested, on theoretical grounds, that future therapies forTourette's syndrome might include glutamate antagonists, although arecent article proposing their use makes no mention of any specificdrugs that might fulfill this role (Chappell et al., Neurol. Clin. May,15(2):429-450, 1997). 4).

A focal dystonia is a recurrent abnormal posturing of some part of thebody. The spasms of focaldystonia can last many seconds at a time,causing major disruption of the function of the affected area. Some ofthe focal dystonias are precipitated by repetitive movements; writer'scramp is the best known example. Focal dystonia can involve the face(e.g., blepharospasm, mandibular dystonia), the neck (torticollis), thelimbs (e.g., writer's cramp), or the trunk. Dystonia can occurspontaneously or can be precipitated by exposure to neuroleptic drugsand other dopamine receptor blockers (tardive dystonia). No systemicdrug therapy is generally effective, but some drugs give partial reliefto some patients. Those most often prescribed are anticholinergics,baclofen, benzodiazepines, and dopamine agonists and antagonists. Themost consistently effective treatment is the injection of botulinumtoxin into affected muscles.

Positron emission tomography has shown that one specific dystonia,torticollis, is associated with neuronal hypermetabolism in the basalganglia. It has been hypothesized that hyperactivity of a motor controlloop involving the cerebral cortex, basal ganglia, and thalamus isresponsible for the abnormal postures and movements (i.e. movements intoand out of abnormal postures) characteristic of dystonia (Galardi etal., Acta. Neurol Scand, September, 94:172-6, 1996). Other studies haveshown abnormal dopaminergic transmission or receptor function inpatients with dystonia (see, e.g. Perlmutter et al., J Neurosci, January15, 17:843-50, 1997). Of note, both too much or too little dopamine maybe associated with dystonia, since patients with Parkinson's disease anddystonia can have the problem both at peak and trough levels of levodopa(Hallett, Arch. Neurol. May, 55:601-3, 1998). It is evident that similarmechanisms may be involved in the pathophysiology of tic disorders andfocal dystonias.

The various focal dystonias tend to respond to the same drugs (Chen,Clin. Orthop, June, 102-6, 1998; Esper et al; Tenn. Med, January,90:18-20, 1997; De Mattos et al., Arq. Neuropsychiatry, March 54:30-6,1996) This suggests that a new treatment helpful for one focal dystoniawould be likely to be helpful for another. Furthermore, the commonsymptoms, signs, and responses to medication of spontaneous (idiopathic)dystonia and neuroleptic-induced dystonia suggest that an effectivetreatment for a drug-induced focal dystonia will be effective for thesame dystonia occurring spontaneously.

Blepharospasm, one of the focal dystonias, is a condition that involvescontinually recurring involuntary eye closure or excessive forcefulblinking. Blepharospasm is one of the most common disorders ofoculomotor function. It is variably regarded as a facial dyskinesia or afacial dystonia. When it occurs together with dystonia of the oral andmandibular regions, with or without involvement of the neck, it isreferred to as Meige syndrome. Blepharospasm can significantly impairvisual function. Patients can become unable to read, to drive anautomobile, or to do any skilled work requiring visual control.Blepharospasm can occur spontaneously (idiopathic blepharospasm) andwith a prevalence that increases with increasing age; most cases arisein the fifth and sixth decades of life (Holds et al., Am. Fam.Physician, June, 43:2113-20, 1991). It also can occur as a sequel toneuroleptic drug treatment (Ananth et al., Am. J. Psychiatry, April,145:513-5, 1988; Kurata et al., Jpn. J. Psychiatry. Neurol., December,43:627-31, 1989; Sachdev et al., Med. J. Aust., March 20, 150:341-3,1989) and perhaps treatment with other classes of psychotropic drugs(Mauriello et al., J Neuropathol, June, 18:153-7, 1998), either alone orin conjunction with tardive dyskinesia or tardive dystonia. Anotherreport of 19 patients with severe tardive dyskinesia, stated thatfrequent eye blinking was the most frequent prodromal sign of thedisorder (Gardos et al., supra, 1988). The oculomotor phenomena ofidiopathic blepharospasm and Meige syndrome are identical with thoseseen in cases induced by neuroleptic treatment. Differences betweenidiopathic blepharospasm and tardive blepharospasm do not involve theocular movements themselves. Patients with idiopathic blepharospasm aremore likely to have a family history of movement disorders, and thosewith tardive blepharospasm are more likely to have movements of otherparts of the body.

Though many substances have been tested for their ability to relieveblepharospasm, injection of botulinum toxin into orbicularis oculimuscles is the mainstay of treatment—(Mauriello et al., Br. J.Ophthalmol, December, 80:1073-6, 1996). These injections weaken themuscles responsible for eye closure, thereby mitigating the involuntarymovements of those muscles. They may also indirectly influenceoculomotor control by the central nervous system, by altering the inputfrom motor nerve afferents. Botulinum toxin injections have becometreatment of choice because of the limited efficacy of the numeroussystemic drug treatments tried to date.

Movements associated with blepharospasm “do not respond to systemic drugtreatment”. In one large case series, only 22% of blepharospasm patientstreated with systemic medications got “marked and persistent relief”(Jankovic et al., Mov. Disord., May, 9:347-349, 1983). In anotherreport, of the 13 patients with blepharospasm who did not do well withbotulinum toxin injections, only 2 showed any improvement when givensystemic drug therapy (Mauriello et al., Clin. Neurol. Neurosurg.,August, 98:213-6, 1996)). Even botulinum toxin injections are not alwaysefficacious. Surgery is sometimes recommended for patients who do notget relief from botulinum toxin injections (Elston et al., J. Neurol,January, 239:5-8, 1992).

Of the systemic treatments, (see, for example, Arthurs et al., Can. J.Ophthalmol: February, 22:24-8, 1987; Casey et al., Neurology, July,30:690-5, 1980; Jacoby et al., Invest. Ophthalmol. Vis. Sci., March,31:569-76, 1990; Michaeli et al., Clin. Neuropharmacol., June, 11:241-9,1988; Ransmayr et al., Clin. Neuropharmacol., February, 11:68-76, 1988;clonazepam, a GABA agonist, was the only drug consistently found useful(Jankovic et al., Ann. Neurol., April, 13:402-11, 1983). A combinationof two GABA agonist agents, valproate and baclofen, was efficacious in asingle case (Sandyk, et al., S Afr Med J, December, 64:955-6, 1983).Tetrabenazine, a dopamine depleting agent, alleviated involuntarymovements in 4 of 6 patients with Meige syndrome, but the patients hadmany undesirable side effects including drowsiness, drooling andParkinsonism (Jankovic, et al., Ann Neurol, January, 11:41-7, 1982).Because of such unpleasant side effects, tetrabenazine has not become awidely-used treatment for blepharospasm, tics or even tardivedyskinesia, despite the absence of other generally effective treatmentsfor these conditions. In sum, though GABA agonists and dopamine receptorblockers have been employed with some benefit in the treatment ofidiopathic blepharospasm, neither type of medication has proved to be agenerally satisfactory treatment.

Because magnesium deficiency can cause neuromuscular excitability(Durlach et al, Magnes Res, June, 10:169-95, 1997), it could potentiallycause or aggravate movement disorders. Ploceniak, (CommunicationsLibres, 91, suppII, 1990) reported, without details, that he had foundmagnesium supplementation useful in patients with bruxism (teethgrinding) and facial tics associated with tetany (susceptibility tomuscle cramps typical of hypocalcemia). He did not, however, suggestthat magnesium supplementation would help patients with Tourette'ssyndrome, or those with tics not due to magnesium deficiency.

There is considerable evidence for abnormalities of magnesium status inpatients with severe mental illness (see for example, Athanassenas etal., J. Clin. Psychopharmacol. August, 3:212-6, 1983; Alexander et al.,Br. J. Psychiatry, August, 133:143-9, 1978; Kirov et al.,Neuropsychobiology, 30(2-3):73-78, 1994; Wang et al, 1997; Yassa et al.,Int Pharmacopsychiatry, 14(1):57-64, 1979). Alexander et al. (supra,1978) found that those schizophrenic patients developing extrapyramidalside effects from neuroleptics had, on average, lower magnesium levelsthan those not having such side effects. Neuromuscular excitability andanxiety are common acute manifestations of magnesium depletion. And,there are theoretical reasons to speculate that magnesium deficiency maycontribute to a wide range of neurodegenerative disorders (Durlach etal. 1997, supra). However there has been no suggestion that magnesiumdeficiency is a cause of tardive dyskinesia, tics, Tourette's syndromeor blepharospasm or that magnesium supplementation can be used tosuccessfully treat or prevent movement disorders.

Although the present day pharmacopeia offers a variety of agents totreat movement disorders, none of these agents can prevent or cure theseconditions. Furthermore, the most effective treatments are oftenassociated with intolerable side effects. There remains a clear-cut needfor new treatments for TD, other tardive movement disorders, tics,Tourette's syndrome, blepharospasm, and other focal dystonias that havegreater efficacy and fewer side effects than those currently available.

SUMMARY OF THE INVENTION

The present invention provides a method for treating movement disordersincluding tic disorders, TS, TD, and focal dystonias, in humans. In oneaspect, the invention provides a method for reducing involuntarymovements characteristic of patients with hyperkinetic or dyskineticmovement disorders by administering a pharmacological agent, that both(i) acts directly or indirectly as an agonist at GABA-A receptors and(ii) decreases NMDA-type glutamate neurotransmission by an indirect ormodulatory mechanism. Specific instances include calciumN-acetylhomotaurinate (acamprosate), magnesium N-acetylhomotaurinate,other salts of N-acetylhomotaurinate, derivatives ofN-acetylhomotaurinate with similar pharmacodynamic effects on GABA andNMDA-type glutamate neurotransmission, and pro-drugs that aremetabolized in the liver, blood, or brain to yield N-acetylhomotaurinateor a derivative with similar pharmacodynamic effects. In another aspect,the present invention provides methods for reducing involuntarymovements characteristic of patients with hyperkinetic or dyskineticmovement disorders by administering more than one pharmacological agentthat, in combination, act to increase GABA-A receptor activity anddecrease NMDA-type glutamate neurotransmission.

The present invention also provides a method for treating movementdisorders by combining memantine, magnesium or a non-competitive NMDAreceptor antagonist with acamprosate, another compound or mixturethereof (specifically including those enumerated in the previousparagraph) that simultaneously decreases the postsynaptic response toglutamate at NMDA-type receptors and also directly or indirectlyincreases GABA-A transmission. In preferred embodiments, magnesium isused as a non-competitive NMDA receptor antagonist.

The present invention demonstrates that magnesium can augment the effectof pharmacological agents used to treat movement disorders includingtics and TD, and, by extension, TS and blepharospasm. Synergisticactivity is shown between magnesium and pharmacological agents that actas NMDA receptor antagonists and simultaneously as enhancers of GABA-Atransmission. Alternatively, magnesium alone is used to reduce symptomsassociated with movement disorders.

In another preferred embodiment, supplementation with magnesium is usedto prevent movement disorders in people already at risk for them, byreducing the risk, or by delaying the onset of the movement disorder forwhich they are at risk. In particular, it is asserted that magnesiumdeficiency is a risk factor for the development of TD in patientsreceiving neuroleptics, and that magnesium supplementation may preventthe development of TD, particularly in patients prone to magnesiumdeficiency, including elderly women, alcoholics, diabetics, peopletaking diuretics, and malnourished individuals.

In other embodiments, any combination of agents that act as NMDAreceptor antagonists together with one or more agents that facilitateGABA-A neurotransmission (by acting as GABA-A receptor agonists, byincreasing GABA-A release, or by increasing the post-synaptic responseto GABA-A receptor stimulation), with or without magnesium, are used fortreatment of movement disorders.

A pill combining agents that act as NMDA-type glutamate receptorantagonists, GABA agonists and magnesium is proposed as a specificvehicle for the delivery of this combined therapy. In addition, otheroral preparations are suggested; the mixture can be delivered in asyrup, elixir, or time release capsule. The latter is suggested as amethod for prolonging the duration of action of a dose of the mixture.

DEFINITIONS

“Tardive dyskinesia”: As used herein “tardive dyskinesia” is meant toinclude tardive dystonia and other movement disorders related tolong-term neuroleptic use. The abbreviation TD may be used in place ofthe term “tardive dyskinesia”.

“Tourette's syndrome”: “Tourette's syndrome” as used herein issynonymous with “Gilles de la Tourette syndromes”, “Tourette syndrome”,“Tourette disorder”, and similar expressions. The abbreviation TS may beused in place of any of these terms.

“Blepharospasm”: As used herein, “blepharospasm” includes Meigesyndrome, which is a combination of blepharospasm and dystonia of theface and/or neck.

“Acamprosate”: As used herein, “acamprosate” refers to calciumN-acetylhomotaurinate. These two terms may be used interchangeably.“N-acetylhomotaurinate” and “acetylhomotaurinate” are usedinterchangeably.

“Acamprosate and related compounds”: “Acamprosate and related compounds”refers to calcium acetylhomotaurinate, magnesium acetyllhomotaurinate,other salts of N-acetylhomotaurinate, acetylhomotaurine base,homotaurine base and homotaurine salts, derivatives of homotaurine oracetylhomotaurine that have similar pharmacodynamic activity withrespect to GABA-A and NMDA-type glutamate transmission, and pro-drugsthat are matabolized in the blood, liver, or brain to yieldacetylhomotaurinate or derivatives with similar pharmacodynamic activitywith respect to GABA-A and NMDA-type glutamate transmission. Acamprosatedecreases the intra cellular response of neurons stimulated by glutamateat the NMDA receptor, and enhances GABA-A transmission, at least in partby an antagonist effect on pre-synaptic GABA-B inhibitory autoreceptors.For ease of expression, I refer to acamprosate and similar compounds as:“GABA agonists and NMDA antagonists”, “GABA-A Agonists andNMDA-antagonists”, “agents that increase GABA transmission and decreaseNMDA-type glutamate transmission”, “GABA agonists and glutamateantagonists”, and “up regulators of GABA transmission anddown-regulators of NMDA-type glutamate transmission”.

“GABA-A transmission”: “GABA-A transmission refers to thepharmacodynamic phenomena associated with the activation of GABA-Areceptors by GABA. Enhancement of GABA-A transmission may involveincreasing the release of GABA, decreasing its metabolism, increasingreceptor binding, or increasing the cellular effects of receptor binding

“GABA-A receptor agonist”: “GABA-A receptor agonist”, as used hereinrefers to molecules that are capable of binding to active or modulatorysites on the GABA-A receptor to enhance GABA-A transmission. (as definedabove)

“NMDA receptor antagonist”: As used herein, “NMDA receptor antagonist”is any molecule that inhibits or diminishes the postsynaptic response ofNMDA-type glutamate receptors to glutamate.

“NMDA-type glutamate neurotransmission”: “NMDA-type glutamateNeurotransmission” is used herein to broadly refer to anything thatwould decrease NMDA-glutamate transmission, whether it acts before thesynapse, at the receptor binding site, within the ion channel, withinthe cell membrane, or inside the neuron. This includes anything thatreduces release of glutamate at synapses with NMDA receptors, alters thebinding of glutamate to NMDA receptors or alters the number of NMDAreceptors.

“Effective”: “Effective” as used herein in reference to dose refers tothe administration of a specific amount of a pharmacologically activeagent tailored to each individual patient manifesting symptoms of aparticular movement disorder (e.g. TD, TS, other tic disorders, orblepharospasm), sufficient to cause a reduction or improvement in any ofthe associated symptoms (including hyperkinesia, dyskinesia or dystonia,and associated cognitive or other mental symptoms), with tolerableadverse effects. Experimentally, doses of acamprosate ranging from 333mg to 666 mg administered three to four times daily are effective. Aperson skilled in the art will recognize that the optimal dose of apharmaceutical agent administered will vary from one individual toanother. Dosage in individual patients should take into account thepatient's height, weight, rate of absorption and metabolism of themedication in question, and the stage of the disorder to be treated, aswell as what other pharmacological agents are administered concurrently.

“Movement disorder”: “Movement disorder”, as used herein, is used torefer to all forms of abnormal and involuntary movements, includingvocalizations. Movement disorders include, for example, tardivedyskinesia (TD), tics, Gilles de la Tourette syndrome (TS), Parkinson'sdisease, Huntington's disease, and focal dystonias such asblepharospasm.

“Tic disorder”: “Tic disorder” as used herein, refers to an abruptrepetitive movement, gesture, or utterance that often mimics a fragmentof purposeful behavior. Tics are characterized by stereotyped,repetitive, but irregularly rhythmic involuntary movements. They includeboth motor tics and vocal (phonic) tics. Tic disorders include, forexample, simple tics, multiple tics and Gilles de la Tourette syndrome,defined as multiple tics with vocalizations.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to prevention and treatment of movementdisorders, including tic disorders, tardive dyskinesia and other relatedconditions. In one aspect of the present invention, I have discoveredthat an agent used in the treatment of abstinent alcoholics, notcontemplated for use in treatment of tardive dyskinesia or othermovement disorders, including Tourette's syndrome and tics, is effectivein reducing the hyperkinesia and dyskinesia of patients with movementdisorders. Several years ago, I hypothesized that TD represents a formof non-linear oscillation in neural circuits involving the basalganglia, and that oscillation might be reduced by agents that blockexcitatory neurotransmission. PET scan studies have demonstratedincreased metabolism in the globus pallidus and primary motor cortex inschizophrenic patients with TD, but not in those without TD (Pahl etal., J Neuropsych Clin Neurosci 7:457, 1995). This suggests that TD isassociated with hyperactivity in a motor control circuit, which might bepart of the putative nonlinear oscillator.

As noted above, I have advanced the hypothesis that agents which act toreduce the gain in a motor control circuit through the striatum, mayhave a beneficial action on TD and related movement disorders (e.g.,Tourette's syndrome and tics). GABA is an inhibitory neurotransmitter inthe striatum. Thus, support for my hypothesis comes from animal evidenceindicating that agents that directly or indirectly stimulate GABAreceptors can decrease neuroleptic-induced dyskinesias (Gao et al. JNeural Transmission 95:63, 1993; Stoessl, Pharmacol. Biochem. Behav.,54:541, 1996). Rats with neuroleptic-induced dyskinesia demonstratedecreased striatal levels of glutamic acid decarboxylase, therate-limiting enzyme in the production of GABA (Delfs et al., Exp.Neurol., 133:175, 1995).

Without limiting the biochemical mechanism of the invention to thatdescribed here, it appears that drugs that act to reduce the gain in thehypothesized oscillator circuit would reduce the involuntary movementsof tardive dyskinesia. GABA, glutamate, and dopamine are the principalneurotransmitters in the circuit. Other neurotransmitters, includingnorepinephrine, serotonin, acetylcholine and endogenous opiates arehypothesized to have indirect actions on the oscillator circuit. In myco-pending patent application, Ser. No. 08/861,801, the teachings ofwhich are incorporated herein by reference, I disclosed that certainantagonists of excitatory neurotransmitters are effective in treatingboth the movement and cognitive disorders associated with TD, tardivedystonia, and related movement disorders

In the current invention, I disclose that acamprosate, a GABA-receptoragonist that also diminishes the postsynaptic response of NMDA-typereceptors to glutamate can ameliorate TD as well as related involuntarymovements and cognitive symptoms. For example, according the theory ofthe present invention, a GABA agonist with concurrent effects onglutamate transmission reduces the severity of the involuntary movementsassociated with TD. Such a GABA agonist alleviates focal dystonias, forexample blepharospasm associated with TD and by extension idiopathicblepharospasm, which is likely to share a common mechanism, in light ofthe response of both to dopamine antagonists, to GABA agonists, and tobotulinum toxin injections. To further this point, an expert onblepharospasm, Dr. Gary Borodic of the Harvard Medical School, statesthat neuroleptic-induced (tardive) blepharospasm is in general lessresponsive to medications than the spontaneous kind (Borodic, personalcommunication, 1998). If this is so, a treatment effective for tardiveblepharospasm is especially likely to be helpful for spontaneousblepharospasm.

Likewise, treatment with acamprosate will likely ameliorate symptomsassociated with Meige syndrome, which is blepharospasm accompanied bydystonic movements of the neck and lower face. Also disclosed in thepresent application is that acamprosate dramatically diminishesdyskinetic movements associated with tic disorders, including bothsingle and multiple tics. Furthermore, I propose that acamprosate andother agents with both (i) decrease NMDA-type glutamateneurotransmission, and (ii) increase GABA-A receptor neurotransmissionare useful in the treatment of a common and severe type of tic disorder,Tourette's syndrome, which is characterized by multiple motor and phonictics.

Acamprosate (calcium N-acetylhomotaurinate) is the calcium salt ofhomotaurine, an analogue of the amino acid taurine. It is usedclinically in the treatment of abstinent alcoholics to reduce or inhibittheir craving for alcohol. Acamprosate, which is chemically similar tothe inhibitory neurotransmitter GABA, is a GABA agonist, particularly atGABA-A receptors. Moreover, it reduces the postsynaptic response ofNMDA-type glutamate receptors and reduces calcium influxes throughvoltage-operated channels. (Wilde & Wagstaff, Drugs, 53:1039-53, 1997)

Acamprosate is a particularly attractive drug for treating chronicmovement disorders, because of its very low toxicity. In controlledtrials for alcoholism treatment involving 3,338 patients, acamprosatehad no severe medical or neurological side effects. Indeed, the rate ofsubject dropout was identical in the group receiving acamprosatetreatment and in the group receiving a placebo (Wilde and Wagstaff,Drugs, June, 53(6):1038-53, 1996). This is in stark contrast to existingsystemic treatments for TD and TS. For these, as noted above,intolerable side effects are common, and impose a major limitation ontheir clinical utility.

The above hypothesis regarding a motor control circuit involving GABA(via GABA-A receptors) and glutamate (via NMDA receptors) implies thatany drug that is a GABA agonist and an NMDA-type glutamate antagonistcan ameliorate dyskinetic movements. Acamprosate (calciumN-acetylhomotaurinate) is a specific example of such a drug for which Ioffer direct evidence in humans of efficacy in the treatment ofdyskinesia. Other examples of such drugs include other salts ofN-acetylhomotaurine, derivatives of taurine and homotaurine with similareffects on GABA and NMDA-type glutamate transmission, and pro-drugs thatare metabolized in the liver, blood, or brain to yieldN-acetylhomotaurinate or related compounds with similar pharmacodynamicproperties.

Accordingly, a preferred embodiment of the present invention providesderivatives of homotaurine and N-acetylhomotaurine effective doses to apatient for treatment of movement disorders. Particularly preferred arederivatives of acamprosate that are readily absorbed from thegastrointestinal tract. Acamprosate is irregularly absorbed from the GItract, in part due to the polar, hydrophilic character of theacetylhomotaurinate ion. It is well known in the art that certainderivatives of drugs may be absorbed better and more reliably becausethey are more lipophilic. For example, esters prepared from theacetylhomotaurinate ion would be more lipophilic, and therefore mighthave greater and more predictable absorption through the membranes ofthe intestinal mucosa. If such an ester were nontoxic and naturallymetabolized in the body, for example, cleaved by enzymes in the blood,liver or the brain, it would be particularly preferred as a vehicle forreliably delivering the acetylhomotaurinate ion to the brain.Furthermore, such derivatives as described above would have, inappropriate dosages, equal or greater efficacy in treating any movementdisorder responsive to acamprosate. Generally, any pro-drug withimproved delivery of acamprosate would be a preferred means of deliveryaccording to the present invention. Additionally a particularlypreferred form of acamprosate would be a derivative of acamprosate witha long half-life. Such a derivative of acamprosate would be clinicallysuperior to acamprosate, because it could be taken once daily, ratherthan three or four times per day, as is necessary when acamprosate isused. An additional approach to lengthening the half-life of acamprosateor a related medication is to deliver it in a time-release capsule.

In other preferred embodiments, these derivatives are used to treatdyskinetic movement disorders associated with prolonged exposure toneuroleptic medications. Additionally, compositions described in thepresent application can be used to treat tardive dyskinesia in abstinentalcohol abusers who are treated with neuroleptics for concurrent mentaldisorders, for example bipolar disorder or schizophrenia. Moreparticularly, the present invention provides treatments that reduce theseverity and duration of various related movement disorders.

Another preferred embodiment of the present invention provides atreatment for focal dystonias. One example of a focal dystonia,blepharospasm, is a target for treatment in the present invention. Asmentioned above, blepharospasm is a condition that involves involuntaryforced eye closure. As mentioned above, blepharospasm can occurspontaneously (idiopathic blepharospasm) or can be a form of tardivemovement disorder. The eye movement disorder of idiopathic blepharospasmis clinically identical to the one that arises following neurolepticexposure and therefore might be expected to respond to the sametreatments that are efficacious for tardive movement disorders. In fact,both disorders are ameliorated, at least in the short term, byneuroleptic drugs and other dopamine antagonists, and both areresponsive to injections of the orbicularis oculi muscles with botulinumtoxin (Casey, Neurology, July, 30:690-5, 1980).

The present invention demonstrates relief of blepharospasm associatedwith tardive dyskinesia by treatment with acamprosate, suggesting thatacamprosate and related compounds and derivatives with combined actionon GABA and NMDA-type glutamate receptors will benefit people withidiopathic blepharospasm and all other focal dystonias, whetherspontaneous or induced by exposure to neuroleptic medications.

In one preferred embodiment of this aspect of the invention, apharmaceutical agent is selected from the group of agents that act asGABA-receptor agonists and also act to decrease NMDA receptor functionby an indirect or modulatory mechanism such as, in a non-limitingfashion, acamprosate calcium (calcium N-acetylhomotaurinate), othersalts of N-acetylhomotaurinate (e.g., magnesium N-acetylhomotaurinate orlithium N-acetylhomotaurinate), acetylhomotaurine base, otherhomotaurine derivatives with similar pharmacodynamic actions on GABA andglutamate transmission, and pro-drugs that are metabolized in the liver,blood, or brain to yield N-acetylhomotaurinate or related compounds withsimilar pharmacodynamic actions on GABA and glutamate transmission. Inanother preferred embodiment, a pharmaceutical agent is selected fromthe group of agents that have the ability to reduce glutamate-producedexcitatory post-synaptic potentials in striatal cells, includingacamprosate and the range of similar compounds and pro-drugs describedpreviously). In other preferred embodiments, a combination of two ormore pharmaceutical agents is selected such that the combination actsconcurrently to augment GABA transmission (particularly via GABA-Areceptors) and to attenuate NMDA-type glutamate transmission (e.g., bynon-competitive inhibition, or by indirect or modulatory effects on NMDAreceptors). A fourth embodiment is to combine such a compound or mixtureof compounds with memantine or a similar non-competitive NMDA-receptorblocking agent described in detail below. The combinations may be eithermixtures, covalently-bound moieties with combined action, or pro-drugsmetabolized in the blood, liver, or brain to release each member of thecombination.

Risk factors for TD include advanced age, diabetes, alcoholism and aprimary psychiatric diagnosis of a mood disorder rather thanschizophrenia. Each of these risk factors also associated with a highprevalence of magnesium deficiency (Durlach, et al., Magnes Res, March,1998; G'amez et al., Sci. Total. Environ., September 15, 203(3):245-511997; Gullestad et al., J Am Coll Nutr, February, 13:45-50, 1994; DeLeeuw et al, Magnes. Res., June, 10:135-41, 1997; Lipski et al, AgeAgeing, July, 22:244-55, 1993; Martin et al., J. Trace. Elem.Electrolytes Health Dis, September, 5:203-11, 1991; Shane et al.,Magnes. Trace. Elem., 10:263-8, 1991-1992; Zorbas et al., Biol. Trace.Elem. Res., July-August, 58:103-16, 1997). Because people that fit theprofile for being at risk for developing TD have an increased risk ofmagnesium deficiency, I hypothesize that magnesium deficiency (per se)is also a risk factor for tardive dyskinesia and other movementdisorders. Therefore, I further assert that magnesium supplementationcan alleviate or prevent movement disorders and potentiate the action ofother treatments, whether or not the individual treated shows tetany orother signs of magnesium deficiency. (See Case Report 4, in whichtreatment for a patient with tardive dyskinesia was enhanced by adding amagnesium supplement.)

Risk of developing a movement disorder can be assessed, according to thepresent invention by administering to a patient a sufficient andnon-toxic dose of magnesium ion (i.e. a “magnesium load”) andsubsequently measuring the amount of magnesium ion excreted in thepatient's urine. More specifically risk of developing a neuroleptic ordopamine receptor blocker-induced movement disorder can be assessed byperforming standard tests of total magnesium status. If magnesiumdeficiency is present, there is a greater than normal retention ofmagnesium load, and diminished excretion of magnesium in the urine. Ifan abnormally low proportion of magnesium is recovered in a 24 hoursample of the patient's urine, the patient is magnesium-deficient and atrisk for developing a movement disorder.

The present invention demonstrates that supplementation with magnesiumcan reduce symptoms associated with a simple tic and augment the actionof acamprosate in treatment of a simple tic (see Case Report 5).Furthermore, magnesium administered together with acamprosate reducessymptoms associated with simple tic better than either magnesium oracamprosate alone. Together, cases 4 and 5 suggest that supplementationwith magnesium ion may be used to successfully treat other types ofmovement disorder.

In preferred embodiments of the present invention, magnesium is used fortreatment of movement disorders (e.g., TD, Tourette's Syndrome, andfocal dystonias particularly blepharospasm). In addition, magnesiumsupplementation can be used to reduce the risk of developing a movementdisorder. In one preferred embodiment, movement disorders may beprevented by magnesium supplementation. In another embodiment, magnesiumsupplementation may delay the onset of a movement disorder in a personidentified as being at risk for developing a movement disorder. In yetanother embodiment, supplementation with magnesium will reduce thesymptoms associated with various movement disorders.

According to the present invention magnesium supplementation willaugment the therapeutic effects of other NMDA-type receptor antagonistsand down-regulators (see Case Report 5). In one preferred embodiment,magnesium is administered with acamprosate (calcium N-acetylhomotaurine)to treat TD and other movement disorders resulting from neuroleptic druguse, tics, Tourette' syndrome, blepharospasm, other focal dystonias, andthe peak-dose dyskinesia of Parkinson's disease. In a particularlypreferred embodiment, the magnesium salt of N-acetylhomotaurine and themagnesium salts of those derivatives of N-acetylhomotaurine thatsimilarly enhance GABA transmission and diminish NMDA-glutamateneurotransmission, are effective treatments for movement disorders.

It will be recognized by those skilled in the art that all conditionsfor which N-acetylhomotaurine is an effective treatment, the magnesiumsalt of N-acetylhomotaurine, and the magnesium salts of thosederivatives of N-acetylhomotaurine that have similar effects on GABAneurotransmission and NMDA-glutamate neurotransmission will also beeffective treatments. Alternatively, any magnesium salt may beadministered with any salt of those derivatives of N-acetylhomotaurineto treat hyperkinetic and dyskinetic movement disorders. In onenon-limiting example, a pill containing the appropriate dose ofacamprosate together with the appropriate dose of magnesium may beformulated and administered to a patient with a movement disorder. Inother preferred embodiments, an agent that has NMDA antagonist activityand GABA agonist activity is combined with the appropriate dose ofmagnesium in a pill. In yet another preferred embodiment, an NMDAantagonist is combined with a GABA agonist and an appropriate dose ofmagnesium in the form of a pill. One of ordinary skill in the art willrecognize that the composition of administration is not limited to apill, but can also be a syrup, an elixir, a liquid, a tablet, atime-release capsule, an aerosol or a transdermal patch.

The ratio of acamprosate to magnesium can be varied to optimize thetherapeutic synergy of the two ingredients. MagnesiumN-aceytlhomotaurinate (Durlach, supra; 1980), with aMagnesium:acetylhomotaurinate ratio of approximately 1:20 by weight,does not optimize the therapeutic effect of the two components. Attypical therapeutic dosages of acetylhomotaurinate, the amount ofmagnesium is too low to have therapeutically-relevant effects onglutamate transmission. In my experience, I have had excellenttherapeutic results from combining a 2 gram daily dosage of acamprosatewith 1 gram of elemental magnesium, given as a salt or chelate. Thiscombination gives better relief of both TD and tics than 2 grams ofacamprosate alone. I have also demonstrated (see case Report 5 below)that a single dose of 300 mg of magnesium will augment the therapeuticeffect of a single 666 mg dose of acamprosate. Allowing for variationsin individual response, and variations in the intestinal absorption ofboth acamprosate and magnesium, I assert that the optimal ratio ofmg:acetylhomotaurinate for an individual patient will be somewherebetween 1:6 and 1:1. Lower ratios of magnesium to acamprosate areunlikely to boost the therapeutic effect of acamprosate significantly,and higher ratios than 1:1 are likely to produce magnesium toxicity (orat least GI intolerance) at a typical daily acamprosate dose of 2 grams.Although magnesium N-acetylhomotaurinate may be slightly moreefficacious than calcium N-acetylhomotaurinate for treatment of ticdisorders, in the present application we are effectively increasing themagnesium content of acamprosate and related compounds by administeringmagnesium ion (as a salt or chelate) in combination with a salt ofN-acetylhomotaurinate, because there is a significant benefit toadministering a higher ratio of magnesium to acamprosate than is presentin the magnesium salt of acamprosate.

The effects of acamprosate are realized within hours after acamprosateadministration. This observation is critically important to thehypothesized mechanism of action of acamprosate in the treatment ofmovement disorders. In 1997, Lidsky et al., (U.S. Pat. No. 5,602,150)described the use of taurine and taurine derivatives, for the preventionof tardive dyskinesia in people taking neuroleptic drugs. In a rodentmodel, animals were given neuroleptics with or without taurine. Overseveral months, the animals receiving taurine were less likely todevelop vacuous chewing movements (VCM), a movement disorder withsimilarity to TD in humans. The mechanism advanced to explain the effectwas a long-term neuroprotective action of taurine, in which taurineblocked the long-term effect of glutamatergic overstimulation ofstriatal neurons. One of ordinary skill in the art would not expect anagent with neuroprotective activity against glutamate-inducedexcitotoxicity to necessarily be efficacious in the treatment of severe,established cases of movement disorder, and to produce benefit withinhours of administration. Indeed, there are well-known situations inneurology where an effective preventive agent can actually aggravate anestablished case of the condition to be prevented. For example, dopamineagonist antiparkinson drugs may delay the onset of dyskinesia inpatients treated with levodopa for Parkinson's disease. Yet, dopamineagonists can aggravate dyskinetic movements once they are established.

Magnesium ions also act as neuroprotective agents, particularly inmodels of neuronal injury mediated by NMDA-type glutamate receptors (Emaet al., Alcohol, February, 15;95-103, 1998; Greensmith et al.,Neuroscience, October, 68:807-12, 1995; Heath et al., J. Neurotrauma,March, 15:183-9, 1998; Hoane et al., Brain. Res. Bull., 45:45-51, 1998;Muir et al., Magnes. Res., March, 11:43-56, 1998; Vanick'y et al.,Brain. Res., April, 789:347-50, 1998). However, the virtually immediatebenefit of magnesium in the treatment of established movement disorderscannot be based on neuroprotection. Rather, immediate and direct effectsof magnesium on neural transmission, including glutamatergictransmission, must be involved. In this connection, note that thedosages of magnesium used for neuroprotection in humans usually are wellabove the I gram per day that was the highest dose used here in thetreatment of movement disorders.

Another aspect of the invention features a method of improving memoryand cognition in humans with TD. A particularly preferred embodiment ofthe present invention is to develop methods for improving cognitivefunction in patients exhibiting TD, specifically to increase memory,span of concentration, and everyday functional performance in activitiesparticularly dependent upon cognition. These improvements in functionare measured both subjectively and objectively. The improvement inmemory can be demonstrated by standard neuropsychological tests. Theimprovement in cognition is demonstrated by performance onneuropsychological tests, including without limitation, the ReyAuditory-Verbal Learning Test, and measurement of Choice Reaction Time,and by subjective indicators of performance at tasks highly dependent oncognitive processes. It will be obvious to one skilled in the art thatnumerous different neuropsychological tests could be employed todemonstrate that cognitive function improved in patients on a treatmentregime that included acamprosate or any of the other above-describedagents, including without limitation: other salts of acetylhomotaurinederivatives of homotaurine and acetylhomotaurine with similarpharmacodynamic effects on NMDA-glutamate and GABA neurotransmission,pro-drugs that are metabolized in the blood, liver, or brain to produceacetylhomotaurinate or derivatives with similar pharmacodynamic effectson NMDA-glutamate and GABA neurotransmission, and mixtures of two ormore compounds that have, taken together, NMDA-glutamate antagonist andGABA agonist effects. All of these entities may also haveneuroprotective actions against glutamate-induced excitotoxic damage,but their virtually immediate beneficial effect on the movementdisorders and cognition, which is reversible if the medication isdiscontinued, cannot be due to such neuroprotective actions.

Another preferred embodiment of the present invention is the developmentof methods for improving tics and, as a consequence, reducing stigma andimproving the quality of life for patients with tics or tic disorderssuch as TS. Yet another embodiment of the present invention is thedevelopment of methods for relieving blepharospasm, and the associatedimpairment visual function implied by frequent, forceful, involuntaryeye closure. A final embodiment of the present invention providesmethods of treating all focal dystonias, whether spontaneous orprecipitated by exposure to neuroleptic drugs and other dopaminereceptor blockers.

One of ordinary skill in the art will recognize that the presentinvention is not limited to a method of treating TD and other ticdisorders with agents that reduce NMDA-type glutamate neurotransmissionand increase GABA neurotransmission via direct effects on GABA and NMDAreceptors. In addition to direct effects on receptor sites, the agentsmay modify NMDA-glutamate and GABA transmission through indirect effectson receptors (i.e., via pre-synaptic effects on neurotransmitterrelease, allosteric modulation of the receptor site, or effects on theintracellular response to the binding of the transmitter to thereceptor), presynaptic effects on transmitter release, or any of avariety of mechanisms. It will be obvious to one skilled in the art thata range of derivatives and pro-drugs all should be therapeuticallyeffective. Anything that shares the effects on glutamate and GABAtransmission hypothesized to underlie the therapeutic effects ofacamprosate is within the scope of the presently claimed invention. Itdoes not matter how a drug, pro-drug or mixture thereof decreasesNMDA-glutamate neurotransmission and increases GABA neurotransmission,only that it improves symptoms associated with TD and tics at tolerablynon-toxic (i.e., free from toxicity unacceptable side effects) doses.

As discussed previously, the inventive treatment can be used to treatany movement disorder characterized by any form of abnormal orinvoluntary movement. Furthermore, the inventive treatment may be usedto improve or eliminate symptoms unrelated to movement that areconsequences of the movement disorder, for example, cognitivedysfunction or abnormalities of motivation, mood, or impulse control.The latter include anxiety, depression, apathy, aggression, andobsessive compulsive behavior. The basal ganglia, including thestriatum, are a point of intersection of motor, cognitive, and emotionalcircuits. Diseases of the basal ganglia frequently involve cognitive,emotional, behavioral, and motivational changes, as well as motordysfunction. I expect that drug treatments effective for TD, tics, andother movement disorders might also alleviate some or all of thenon-motor symptoms. In general, treatments for diseases of the basalganglia do have non-motor effects. For example, dopamine agonistantiparkinson drugs not only increase the rate of movement of patientswith Parkinson's disease, they also improve mental processing speed.When the addition of magnesium increases the effect of a drug treatmenton the motor manifestations of a movement disorder, it may also increasethe effect of that treatment on the non-motor manifestations.

The present invention will now be illustrated by the followingnon-limiting examples.

EXAMPLES Case Report 1

A 45-year old woman had long-standing TD, originally induced by sevenyears exposure to amoxapine, an antidepressant drug with neurolepticeffects. The patient's irregularly-rhythmic movements consisted offorced eye blinking (blepharospasm), thrusting of the tongue forward andfrom side to side, tongue twisting, grimacing, shoulder shrugging, andtensing of the platysma muscles of the neck. (Had the patient's symptomsnot been associated with neuroleptic exposure, a subset of her movementscould be characterized as the Meige syndrome of oromandibular dystoniawith blepharospasm). The patient is a semi-professional musician; thedyskinetic movements were accompanied by significant occupationaldisability, including difficulty reading music or text and difficultyplaying woodwind instruments. Much of her reading impairment was due tofrequent involuntary blinking and eye closure. She had impairedattention, concentration and memory compared with her performance beforethe onset of TD. She had significant fatigue, and usually required restat some point during each day. The patient was diagnosed with TD by aboard-certified neurologist with extensive experience in evaluatingneuroleptic-induced side effects.

The patient's dykinesia and dystonia worsened after the amoxapine wasdiscontinued. Palliative treatment with alprazolam (an anxiolytic andGABA agonist via modulation; dosage 0.25 mg four times a day) andtrihexyphenidyl (an anticholinergic antiparkinson drug that inhibitsdopamine re-uptake at synapses; dosage 2 mg twice a day) was prescribedby another physician. This combination produced minimal improvement. Thepatient began treatment with me in the winter of 1992 and was maintainedon trihexyphenidyl for an additional 18 months. Trihexyphenidyl was thendiscontinued without a change in her involuntary movements. During 1993,alprazolam was increased to 0.5 mg four times a day, to treat mildsymptoms of anxiety; the change in dosage had no detectable effect onthe patient's involuntary movements. Treatment trials with buspirone,sertraline, verapamil, and vitamin E in 1992 either produced littlebenefit or were not tolerated at doses that only slightly reduced herinvoluntary movements. None of these drugs significantly improved thepatient's everyday function, i.e., her performance at reading text ormusic, her stamina or her ability to concentrate. The first drug thatprovided significant and sustained benefits was nimodipine, a blocker ofL-type calcium channels, that indirectly reduces dopaminergic activity(Bonci et al; J. Neurosci., September 1, 18(17):6693-703 1998)

Beginning in 1993, nimodipine was administered at a dosage of 30 mg fourtimes a day. Initially, her other medications were maintained unchanged.This regime reduced the patient's involuntary movements by about 50%.Unfortunately, the patient experienced adverse effects, includingdizziness, lightheadedness, and palpitations. Also, she had nosymptomatic improvement in cognitive function. There was a meaningfulimprovement in her ability to read and to play music. However, even withthis improvement, she could read text or music for no more than 30minutes at a time, before fatigue or blepharospasm prevented her fromcontinuing.

In 1995, memantine came to my attention as a relatively non-toxic NMDAreceptor antagonist. In view of my hypothesis about the pathophysiologyof tardive dyskinesia, I thought that memantine might be beneficial inits treatment. Nimodipine was discontinued, and the patient was begun onmemantine at a dosage of 10 mg twice a day. The involuntary movements ofthe patient's TD were reduced within 24 hours of administration ofmemantine, to a substantially greater degree than had been observed withnimodipine. Adverse effects included a sense of mild intoxication.Adjustments to the therapeutic regime were made such that the drug wasreduced to 5 mg three times a day, with the result that the therapeuticbenefits were maintained without perceptible side effects. In addition,the patient reported improved energy, attention, and concentration.Memantine was the patient's primary treatment for TD for the next 1½years, until I became aware of acamprosate as an indirect NMDAantagonist with the added benefit of GABA agonism.

Prior to treatment with acamprosate, the patient's involuntary movements(on an optimal dose of memantine) consisted of eye blinking, puckeringof the cheeks, writhing of the tongue and tensing of the platysma. Theseinvoluntary movements were usually mild and occasionally moderate inintensity. The movements had been substantially more severe in the past,but had been reduced significantly during the two-year course oftreatment. Moreover, the patient's involuntary movements wereaccompanied by mild but definite cognitive impairment. The patient'smost prominent cognitive symptom was difficulty sustaining concentrationlong enough to read more than a few pages of text.

The patient was taken off of memantine and treated with acamprosate at adose of 333 mg four times a day. On acamprosate, the patient'sinvoluntary movements (forced eye blinking (blepharospasm), thrusting ofthe tongue forward and from side to side, tongue twisting, grimacing,shoulder shrugging, and tensing of the platysma muscles of the neck)became imperceptible.

In addition, the patient's cognitive function improved significantlywhen measured both subjectively and objectively. On acamprosate, thepatient was able to sustain concentration for prolonged periods. Forexample, she could now read a book for over an hour at a time, with goodrecall of what she had read. The patient's cognitive improvement wasalso assessed using formal neuropsychological measures. The patient wastested while on the drug, then taken off of the drug and tested two dayslater. On the drug, the patient was able to recall 13 of the 15 itemsafter a short delay as well as 13 of the 15 items after a long delay, asmeasured by the Rey Auditory Verbal Learning Test. This was incomparison to the patient's ability while off the drug to recall only 7of the 15 items after a short delay as well as 8 of the items after along delay in tests performed. In addition, the patient was able torecognize all 15 of the items while on acamprosate but while off thedrug (and while having been off of memantine for over 2 months) thepatient could only recognize 10 of the items. The order of testing wouldgive the advantage of familiarity to the off-drug condition.Nonetheless, the difference in favor of the on-drug condition wassubstantial.

Comparison with other neuropsychological tests demonstrated that theimproved cognitive findings shown while the patient was on acamprosatewere not explained by a nonspecific lack of effort or to concentrationduring off-drug condition. These additional tests, which reflect basicattention and psychomotor speed, showed that the patient actually hadslightly better results off acamprosate. The tests showing such resultsincluded Simple Reaction Time, the Trail Making Test (both parts) andthe Paced Auditory Serial Addition Test (PASAT). Choice reaction time, atest requiring both basic attention and concentration on a specific taskthat must be kept in mind, was slightly better on acamprosate,consistent with the hypothesis that general cognitive function, asopposed to simple attention, improves with acamprosate treatment.

The following tables report on the results of the neuropsychologicaltests (Drug I is memantine and Drug II is acamprosate):

TABLE 1 REACTION TIME, PSYCHOMOTOR SPEED, & MOTOR FUNCTIONING FOR DRUG I(MEMANTINE) AND DRUG II (ACAMPROSATE) Sep. 25, 1997 Feb. 23, 1996 ONApr. 8, 1996 OFF Sep. 23, 1997 ON OFF TESTS Feb. 23, 1994 DRUG I DRUG IDRUG II DRUG II Simple Reaction Time^(a) 1500 Green NA 212 msec 332 msec261 msec 234 msec 1500 Red NA 224 msec 276 msec 264 msec 241 msec  500Green NA 284 msec 343 msec 286 msec 272 msec  500 Red NA 266 msec 382msec 272 msec 237 msec Choice Reaction Time^(a) 1500 Green NA 365 msec542 msec 408 msec 442 msec 1500 Red NA 422 msec 643 msec 379 msec 435msec  500 Green NA 362 msec 603 msec 382 msec 425 msec  500 Red NA 421msec 557 msec 426 msec 413 msec PASAT^(a) 2.4 sec ISI errors 17/49 13/4915/49  4/49  0/49 2.0 sec ISI errors 17/49 17/49 21/49  1/49  1/49 1.6sec ISI errors 11/49 21/49 22/49 11/49  4/49 1.2 sec ISI errors 17/4928/49 25/49 13/49 11/49 Digit Symbol^(b) NA 34 20 NA NA Trails ASeconds^(a) 25″ 28″ NA 20″ 16″ Errors^(a)  1  0 NA  0  0 Motor FunctionsGrooved Functions DH = 68″ DH = 71″ NA DH = 61″ DH = 59″ sec.^(a) NDH =82″ NDH = 70″ NDH = 70″ NDH = 76″ DH = right Finger Tapping^(b) DH =58.8 DH = 59.3 NA NA NA NDH = 41.6 NDH = 48.5 Grip Strength^(b) NA DH =17.7 NA NA NA NDH = 21.7 Note: ^(a)lower score indicative of betterperformance ^(b)higher score indicative of better performance

TABLE 2 EXECUTIVE, ATTENTION, VISUOCONSTRUCTIONAL & VISUAL MEMORY TASKSFOR DRUG I (MEMANTINE) AND DRUG II (ACAMPROSATE) Feb. 23, Apr. 8, Sep.23, Sep. 25, Feb. 23, 1996 ON 1996 OFF 1997 ON 1997 OFF TESTS 1994 DRUGI DRUG I DRUG II DRUG II 1. Trails B Seconds^(a) 56″  118″ NA 43″ 39″Errors^(ab) 0  0 NA 0 0 Verbal Fluency Letter (CFL)^(b) NA Total = 70 NANA NA Per = 2^(b) Category NA Total = 25 NA NA NA (Animals)^(b) Per =0^(b) Figural Fluency Unique NA 124 99 NA NA Designs^(b)Perseverations^(a) NA  8 4 NA NA 2. CPT - with    conditions   (Vigilance) Commission 0 NA NA 0 0 errors^(a) Omission 0 NA NA 0 0errors^(a) Wrong^(a) 3 NA NA 3 0 Correct^(b) 50/50 NA NA 100/100 100/1003. Rey-    Osterrieth    Complex    Figure Copy Presence NA  20 17 NA NA& Accuracy^(b) Copy NA  5 4 NA NA Organization^(b) Immediate NA −55−47.1 NA NA Retention^(b) Delayed NA   −11.1 22.2 NA NA Retention^(b)Note: ^(a)lower score indicative of better performance ^(b)higher scoreindicative of better performance

TABLE 3 MEMORY TESTING FOR DRUG I (MEMANTINE) AND DRUG II (ACAMPROSATE)Feb. Feb. 23, Apr. 8, Sep. 23, Sep. 25, 23, 1996 ON 1996 OFF 1997 ON1997 OFF TESTS 1994 DRUG I DRUG I DRUG II DRUG II California VerbalLearning Test 16- items List A 1-5 total NA 53 40 NA NA (80 max)^(b)List A Trial 1^(b) NA 7 6 NA NA List A Trial 5^(b) NA 13 9 NA NA ListB^(b) NA 7 5 NA NA Short-Delay Free NA 10 4 NA NA Recall^(b) Short-DelayCued NA 13 9 NA NA Recall^(b) Long-Delay Free NA 12 7 NA NA Recall^(b)Long-Delay Cued NA 15 8 NA NA Recall^(b) Perseverations^(a) NA 23 4 NANA Intrusions^(a) NA 6 0 NA NA Recognition Hits^(b) NA 16 14 NA NA FalsePositives^(a) NA 3 0 NA NA Rey-Auditory Verbal Learning Test 15-itemsList A 1-5 total NA NA NA 63 57 (75 max)^(b) List A Trial 1^(b) NA NA NA10 9 List A Trial 5^(b) NA NA NA 14 14 List B^(b) NA NA NA 8 9Short-Delay Free NA NA NA 13 7 Recall^(b) Long-Delay Free NA NA NA 13 8Recall^(b) Perseverations^(a) NA NA NA 5 0 Intrusions^(a) NA NA NA 0 3Recognition Hits^(b) NA NA NA 15 10 False Positive^(a) NA NA NA 1 2Note: ^(a)lower score indicative of better performance ^(b)higher scoreindicative of better performance

In addition to increased cognitive ability, the patient also experiencedan increase in stamina while taking acamprosate. Prior to beginning theacamprosate regime, the patient was fatigued by the end of theafternoon, requiring rest in order to be alert in the evening. Thisfatigue was significantly decreased while on the acamprosate regime,with a corresponding improvement in fatigue-related cognitive function.On acamprosate, the patient no longer needed to rest during the day inorder to be alert and active during the evening.

To verify that the acamprosate was related to the patient's improvementin controlling movement disorders, cognitive function and stamina, thepatient was removed form the acamprosate regime (as well as thememantine regime) for a period of four weeks. During the initialtwo-week period off acamprosate, the patient's involuntary movementsgradually returned to her pre-acamprosate, off-memantine baseline.(While the patient's off-drug baseline was less severe than it was whenshe started on memantine two years earlier, her movements still weresevere enough to interfere significantly with her everyday functioning.)From that point on, until acamprosate was re-instituted, she showedcontinual mild-to-moderate grimacing, tensing of the platysma, andforced eye closure. These involuntary movements worsened still furtherduring periods of stress or fatigue. Moreover, the patient fatigued muchmore easily, to a degree that noticeably reduced her everydayfunctioning. Subjectively, the patient reported that concentration andmemory both decreased.

Within two days of re-instituting treatment with acamprosate, thepatient reported that her energy, stamina, concentration and memory hadimproved to the level experienced during her prior treatment withacamprosate. Two months after reinstitution of acamprosate, thepatient's involuntary movements were absent except for very mildmovements during times of stress.

In July 1998, this patient participated in a trial of magnesiumsupplementation as an adjunct to her treatment with acamprosate. Duringa 7 day baseline peiod on Campral Cacamprosate 333 mg four times a dayplus alprazolam 0.25 mg four times a day, she noted six episodes ofinvoluntary movements involving the face and neck, 2 moderate and 4mild. For the following 10 days she added 250 mg three times a day ofchelated magnesium. During the period of magnesium supplementation, shenoted no involuntary movements.

Summary

This example demonstrates that efficacious treatments for TD includememantine and acamprosate. Both treatments improve cognition andfunction as well as involuntary movements. Furthermore, both memantineand acamprosate relieve blepharospasm and Meige syndrome associated withmore extensive tardive movement disorders. Finally, oral magnesiumadministration, given together with acamprosate at a ratio of 1:1.8 byweight, augments the therapeutic effect of acamprosate on theinvoluntary movements of TD.

Case Report 2

A 79-year old woman had long-standing TD following decades of treatmentwith the neuroleptic drug perphenazine. Her involuntary movementscomprised bilateral chorea of the upper extremities, plus writhing ofthe tongue and tongue-biting. Both of the latter movements led to a verysore tongue. In addition, the patient experienced impairment of hershort-term memory, which was attributed primarily to cerebrovasculardisease.

Following treatment with memantine the patient's voluntary movementsimproved, but continued at a mild-to-moderate level. She also continuedto have a sore tongue. Her cognitive symptoms did not improve. Inaddition to memantine, the patient regularly took antiepileptic drugs(gabapentin and lamotrigine), antiplatelet agents (aspirin andticlopidine), as well as medications for hypertension, glaucoma andgastrointestinal symptoms (isosorbide mononitrate, metoprolol, timololeye drops and olsalazine). These various drugs did not affect thepatient's involuntary movements or cognitive symptoms; there was nonoticeable change in either one at the time that each of theabove-mentioned drugs was instituted.

The patient was placed on a treatment regime that includedadministration of 666 mg of acamprosate, three times daily. In thiscase, acamprosate was added to the patient's regimen, which continued toinclude memantine. Once the patient began taking acamprosate, her choreaand tongue-biting stopped completely, and the writhing movements of thetongue diminished substantially. Subjectively, the patient's memoryimproved to the extent that her long-term bridge partner stated thatpatient was noticeably better at remembering cards during the play ofduplicate bridge. Despite past evidence from formal testing that thepatient had impaired short-term memory, she performed normally on atwo-sentence memory task, which involved testing the patient's recallability using two sentences containing 13 separate details. On thetwo-sentence memory task, within three attempts the patient was able torecall 9 details and, using a multiple choice format, was able to recalla total of 11 details. Recall of 9 details on the third attempt would benormal for a middle-aged adult, let alone one in her 80s at the time oftesting.

After a full year on memantine and acamprosate, the memantine wasdiscontinued, with little change in the patient's symptoms. Onacamprosate 666 mg three times a day, persistent symptoms included mildchoreatic movements on the hands, mild involuntary movements of thetongue and jaw, and soreness of the tongue disproportionate to thevisible involuntary movements.

Magnesium oxide, 250 mg three times a day, was added, each dose beingtaken together with the acamprosate. The movements and the tonguesoreness improved further. The effect was definite: movements worsenedwhen magnesium oxide was stopped and improved when it was restarted.After a month on magnesium, the dosage of acamprosate was increased to666 mg four times a day, with 250 mg of magnesium oxide given togetherwith each dose. On this regimen, the tongue movements and tonguesoreness were completely eliminated. The only residual sign of TD was amild degree of involuntary movement of the hands.

Summary

Magnesium and acamprosate are both efficacious treatments of tardivedyskinesia when administered alone. More specifically, Case Report 2demonstrates that acamprosate can improve both the involuntary movementsassociated with TD as well as the associated cognitive impairment, in apatient in whom memantine improves involuntary movements but notcognition. Furthermore magnesium, when administered with acamprosate canaugment the efficacy of acamprosate in the treatment o TD. In this case,the combination of acamprosate and magnesium was efficacious at anmagnesium:acamprosate ratio or 1:2.66.

Case Report 3

A 56-year old female professor of nursing had Parkinson's disease sinceher late 30s. The patient's Parkinson's disease was treated usinglevodopa/carbidopa and bromocriptine. The patient's profession requireda high level of mobility and physical effort, but taking a sufficientdosage of the levodopa/carbidopa to allow adequate physical functioningat work resulted in the patient demonstrating severe peak-dosedyskinesia. The patient's manifestations of peak-dose dyskinesiaconsisted of writhing movements of the upper trunk, jerky lateral androtatory movements of the neck, and chorea of both upper extremities.The patient accepted these involuntary movements because lower dosagesof levodopa-carbidopa left her too rigid and hypokinetic to perform herjob.

Prior to beginning treatment with acamprosate, the patient was on anantiparkinson treatment regime that consisted of 1 mg of pergolide threetimes a day, 5 mg of selegiline twice a day, and a combination oflevodopa/carbidopa consisting of 550-600 mg of levodopa and 125-150 mgof carbidopa administered in divided doses. Concurrent medications thatdid not appear to affect her Parkinsonism or dyskinesia consisted ofbethanecol, sertraline, carbamazepine, conjugated estrogens andmedroxyprogesterone. (As with the additional medications mentioned inCase 2, there had been no noticeable change in the patient'sParkinsonism or dyskinesia after the introduction of each of the drugslisted.) The patient also received 10 mg of memantine three times a day,which had previously reduced her dyskinetic movements from severe tomild-to-moderate.

The patient began acamprosate as an addition to the antiparkinson regimedescribed above. Initially, the patient received 666 mg of acamprosateadministered three times a day. Two weeks later the regime was adjustedsuch that the patient received 333 mg of acamprosate four times a day,taking one 333 mg pill with each daytime dose of 100 mg levodopa and 25mg carbidopa. The patient's bedtime does of controlled-releaselevodopa-carbidopa (200 mg of levodopa and 50 mg of carbidopa) wascontinued, but were given without acamprosate. As soon as acamprosatewas added to her regimen, the patient's severe peak-dose dyskinesia wasreduced from moderate to mild intensity, and there were periods of up totwo hours following each dose during which there was no dyskinesia atall. There was no decrease in the efficacy of the levodopa/carbidopatreatment of her hypokinesia and rigidity. On acamprosate, the patientexperienced longer periods of good motor function, and she now had noperiods at all where her motor function was inadequate for work orsocial activity. The reduction of the dyskinesia to a minimal level ledto a substantial improvement in purposeful motor function of the upperextremities. To confirm that the patient's improvement was due to theadministration of acamprosate, the patient was taken off theacamprosate. Within one day of stopping acamprosate, the patient'sdyskinetic movements were as severe as they had been before acamprosatewas first given. Upon re-instituting acamprosate, the patientexperienced an immediate reduction in her dyskinetic movements. Duringthe period off acamprosate, an attempt was made to replace acamprosatewith baclofen (a GABA-receptor agonist) at a total daily dose of 30 mg,and then with baclofen at a total daily dose of 60 mg. These doses ofbaclofen were high enough to produce sedation and nausea, but they hadno beneficial effect on the patient's dyskinesia. Additional improvementin the dyskinesia was subsequently obtained by replacing the pergolidewith 1 mg. of pramipexole administered three or four times a day.

Several months later, magnesium (300 mg elemental magnesium, as a mixedchelate), was added to the regimen. It was taken three times a day,together with a one of the patient's regular doses oflevodopa/carbidopa. There was an immediate reduction of the severity ofdyskinesia. To establish whether the improvement was due to magnesium,the magnesium was stopped after several weeks. Within 2 days, thedyskinesia was definitely worse.

Summary

Case Report 3 demonstrates that memantine and acamprosate can amelioratethe peak dose dyskinesia of treated Parkinson's disease. The efficacy ofmemantine and acamprosate in the treatment of the peak dose dyskinesiaof Parkinson's disease can furthermore be augmented by co administrationof magnesium at a ratio of 1:1.48 by weight with acamprosate.

Case Report 4

A 37-year old man had extremely severe tardive dyskinesia and dystonia,as a result of over 15 years of treatment of bipolar disorder withlithium and an assortment of neuroleptics. His involuntary movementsconsisted of forced extension of the trunk, torsion of the lower legs,plantar flexion of the left foot, chorea of both arms, writhing of thetongue and grimacing. In addition, he had profuse sweating associatedwith the involuntary movements. To sit still in a chair, he had toforcefully grip both arms. In the chair, forced extension of the trunkpractically lifted him out of the chair. His trunk and leg movements ledto impaired balance, with a staggering gait and frequent near-falls. Thecontinual severe movements were associated with impairment inconcentration, which made his work less efficient. By virtue of talentand intelligence, however, he was able to work competitively as asoftware engineer. Because his bipolar disorder remained an activeproblem, continued neurolepric treatment was necessary to maintain hismental health. He was maintained on lithium carbonate 300 mg three timesa day, and risperidone 4 mg per day.

His movement disorder had been treated with benzodiazepines,anticholinergics, and dopamine agonists, all without meaningful benefit.He was then treated with acamprosate, first at a dosage of 333 mg threetimes a day, and then at a dosage of 666 mg three times a day.Acamprosate therapy was then augmented with magnesium sulfate, 300 mgthree times a day. After several weeks, memantine 10 mg three times aday was added, but memantine was discontinued after a few days becauseit aggravated his movement disorder.

At one point during his treatment, the patient ran out of acamprosate,and was without it for three days. After 24 hours off acamprosate, hismovement disorder returned to its (severe) baseline. 72 hours afterresuming acamprosate, he regained his previous level of benefit.

The patient maintained a weekly log of symptoms, which is reproducedhere as Table 4. The table shows that:

-   -   1) Acamprosate therapy was associated with improvement in all of        his symptoms. For several of his symptoms—trunk movement,        balance, and sweating 666 mg of acamprosate three times a day of        acamprosate was more efficacious than 333 mg three    -   2) The addition of magnesium was associated with further        improvement in several symptoms, i.e., movements of the face and        tongue, neck and limbs;    -   3) Benefits of acamprosate increased with continued therapy;    -   4) Mental function, as indicated by subjective memory, improved        along with the involuntary movements;    -   5) The addition of memantine aggravated the involuntary        movements.

The patient's self-ratings understate the degree of improvement noted bythree physicians (two neurologists and one psychiatrist) who examinedthe patient before and after treatment with acamprosate and magnesium.Before treatment, he was unable to sit in a chair without gripping thearms, writhing and rocking wildly. After treatment, he was able to walkacross a room carrying a cup of coffee and not spilling any.

TABLE 4 PATIENT SELF-REPORT OF TD TREATMENT EFFECTS - CASE 4 Regimen 1.Acamprosate 333 mg three times a day 2. Acamprosate 666 mg three times aday 3. Acamprosate 666 mg three times a day + Magnesium    sulfate, 300mg three times a day 4. Acamprosate 666 mg three times a day + memantine10 mg    three times a day Symptoms Severity of face and tonguemovements (10 is worst) Severity of trunk movements (10 is worst)Difficulty maintaining balance (10 is worst) Sweating (10 is worst)General well being (10 is best) Memory and concentration (10 is best)Side Effects(10 is none) Week Number 0 1 2 3 4 5 6 7 8 9 Regimen #baseline 1 2 3 3 3 3 3 4 3 Scale Face/tongue 7 5 7 6 4 2 3 3 6 4 Neck 77 7 6 5 5 4 3 6 4 Trunk 9 8 6 6 4 4 4 5 7 4 Limbs 8 6 7 6 4 2 3 5 7 4Balance 7 7 5 6 6 4 4 4 6 4 Sweating 10 8 5 6 5 3 4 4 5 4 Well-being 7 88 8 9 9 9 9 7 9 Memory 8 9 9 9 9 9 9 9 9 9 Side effects* 7 7 9 9 9 9 9 79 *The only significant side effect was nausea and vomiting, which thepatient experienced for the first day after starting acamprosate, thefirst day after increasing the dose of acamprosate, and the first dayafter adding memantine.Summary

Acamprosate is efficacious in the treatment of severe tardive dyskinesiaand dystonia. Administration of magnesium with acamprosate enhances thetherapeutic action of acamprosate in the treatment of severe TD andtardive dystonia. In the case reported, a good effect was obtained at amagnesium:acamprosate ratio of 1:2.22. Memantine, though often effectivein the treatment of tardive dyskinesia, actually can aggravate it incertain individuals, such as the one described in Case 4. Treatment withacamprosate, with or without magnesium, can help alleviate a movementdisorder that is aggravated by memantine. Additionally, this case reportdemonstrates that acamprosate, administered with or without magnesium,can relieve involuntary movements and other symptoms in patients withtardive movement disorders who continue to receive neuroleptics fortheir mental disorder.

Finally, Case 4 illustrates the point that a treatment that prevents thedevelopment of involuntary movements in an animal model of TD (i.e.memantine, see Andreassen et al. supra) may be of no benefit at all intreating humans with established TD.

Case Report 5

A 46 year old man had simple tic of the neck that involved forcefulextension and rotation of the neck to the right. The tic had started inthe context of therapy of depression with dextroamphetamine andpramipexole, a dopamine agonist drug. The tic occurred from 20-50 timesper hour, with greater frequency when he was tired or under stress.

He was initially treated with 666 mg of acamprosate three times a day.Within 24 hours after the start of acamprosate therapy, the frequencyand severity of the tic decreased dramatically, to a rate of less than 5per hour. The patient often was free of tics completely for 2 to 3 hoursafter each dose of acamprosate, after which time the tic would verygradually return. The dose was then raised to 666 mg four times a day.On this dose, rates of more than 5 per hour occurred only underunusually stressful circumstances, and there were frequent tic-freeperiods of 4 hours or more. If acamprosate was omitted for a full day,the frequency of tics rapidly increased, to over 10 an hour. On a secondday without acamprosate, the rate of tics was again over 20 per hour.

He then added chelated magnesium, at a dosage of 300 mg of elementalmagnesium 3 times a day. With magnesium supplementation, the average ticfrequency dropped to 6 hour or less. When 666 mg of acamprosate wasgiven three times a day was given together with magnesium 300 mg threetimes a day, the usual tic-free period after each acamprosate doseincreased from approximately 3 hours to approximately 5 hours.

Summary

Acamprosate is efficacious in the treatment of a simple tic. Theefficacy of acamprosate is enhanced by concurrent administration ofmagnesium. In this case, a good effect was obtained at amagnesium:acamprosate ratio of 1:2.22. By extension, acamprosate shouldbe efficacious in the treatment of multiple tics and Gilles de laTourette syndrome.

Case Report 6

A corresponding physician the United Kingdom recently reported to me onthe treatment of a 47-year old woman with chronic schizophrenia andsevere tardive dyskinesia. As in Case 1, the patient's involuntarymovements included severe blepharospasm. In addition, she hadinvoluntary rhythmic peri-oral movements, and chorea-like movements ofboth hands, like the patient in Case 2. She had no cognitive complaints,nor were cognitive abnormalities noted on routine psychiatricexamination.

The patient had developed symptoms of paranoid schizophrenia in 1991, atage 40. The symptoms of psychosis included auditory hallucinations,bizarre delusions, and persecutory fears. She was started on oralhaloperidol as an outpatient in July 1992 and had an acute dystonicreaction to the drug. She was subsequently hospitalized and stabilizedon fluphenthixol decanoate, a depot neuroleptic given by intramuscularinjections. Symptoms of TD developed in November, 1994, after 28 monthsof neuroleptic therapy. Switching the patient to an atypicalneuroleptic, olanzapine or risperidone, did not eliminate her TD.Beginning in October 1997 the patient was treated for her schizophreniawith 2 mg of risperidone alone. On this modest dose of an atypicalneuroleptic, she had severe symptoms of TD for which she eagerly soughttreatment.

Memantine was started on November 28, 1997 at a dose of 5 mg per day,increased after 7 days to 5 mg twice a day, and after another 7 days to5 mg three times a day. After the first two weeks of memantine treatment(an on 5 mg twice a day) there was marked improvement in blepharospasm,though the movements started to return just before the second dose ofthe day was due. Two weeks later, on 5 mg three times a day, improvementwas more sustained, with virtually no involuntary movements noted at thepeak of a given dose of memantine, and only mild movements noted when adose was due. Further dosage increases were attempted to completelyabolish the involuntary movements. The maximum dose attainable withoutside effects was 10 mg twice a day; above that level the patient hadcomplaints of dizziness. That dose of memantine was maintained throughMay of 1997. At that point, after 6 months of treatment with memantine,the patient had no blepharospasm or limb chorea, and only mild peri-oralmovements.

In May 1998 the patient was started on acamprosate, in pursuit ofcomplete elimination of her involuntary movements. Initially,acamprosate 333 mg three times a day was added to memantine 10 mg twicea day. With the addition of acamprosate, peri-oral movements wereeliminated, and the patient was essentially free of involuntarymovements. Memantine was discontinued in August 1998; the patientcontinued free of involuntary movements on acamprosate alone.

Summary

Both memantine and acamprosate can alleviate the involuntary movementsof TD in patients with chronic schizophrenia who continue to requireneuroleptic therapy. Both drugs can relieve severe neuroleptic-inducedblepharospasm. Acamprosate can relieve involuntary movements of TD thatdo not respond to memantine at doses tolerated by the patient. Theresponse of drug-induced blepharospasm to these two agents suggests thatmemantine and acamprosate will be helpful in the treatment of idiopathic(spontaneous) blepharospasm. By extension, they can be expected to beuseful in the treatment of other focal dystonias.

Discussion

The patients discussed in cases 1-6 above all exhibited a markeddecrease in the frequency and severity of dyskinetic movements. Reliefof symptoms began within 48 hours of administration of acamprosate, and,if a patient discontinued acamprosate, symptoms returned immediately.Those patients who previously exhibited cognitive disorders showedfunctionally significant improvement in cognitive function afterbeginning treatment with acamprosate (See cases 1, 2, and 4). Thisevidence supports my novel hypothesis that acamprosate, or a derivativewith similar pharmacodynamic actions, will be helpful in the treatmentof hyperkinetic movement disorders, including dyskinesias and dystonias,and the cognitive impairment associated with them. Acamprosate andsimilar drugs have simultaneous actions on GABA neurotransmission andNMDA-type glutamate neurotransmission that may be synergistic in regardsto the therapy of hyperkinetic, dyskinetic and dystonic movementdisorders. To the extent that other related compounds and mixtures ofcompounds have similar simultaneous effects upon GABA and glutamateneurotransmission, these related compounds may have the same or similaraction on movement disorders and their associated cognitive impairments.Related compounds include, but are not limited to other salts ofN-acetylhomotaurinate (e.g., magnesium N-acetylhomotaurinate),acetylhomotaurinate base, homotaurine, derivatives of these compounds,and pro-drugs metabolized in the liver, blood, or brain to yieldacetylhomotaurinate or analogues with similar pharmacodynamic effects onGABA and NMDA-type glutamate neurotransmission. Additionally, anyderivatives or pro-drugs that are easily absorbed after oraladministration, or have a long half-life are particularly desirable.

Acamprosate also has benefits for treating hyperkinetic or dyskineticmovement disorders other than TD. Case 3 shows it is useful inalleviating the peak-dose dyskinesia of Parkinson's disease treated withlevodopa. Case I shows acamprosate can be used successfully to treatblepharospasm (a focal dystonia) and Meige syndrome when these areassociated with TD, and suggests that it can be used successfully totreat idiopathic blepharospasm and Meige syndrome. Case 4 suggests thatacamprosate is efficacious in treating simple tics, and, by extension,multiple tics and Gilles de la Tourette syndrome. By extension,acamprosate will likely benefit patients with movement disorders notinduced by neuroleptics, that show clinical symptomatology identicalwith those of a neuroleptic-induced (tardive) movement disorder. Inparticular, it may be efficacious in treating any of the focaldystonias, and in treating the involuntary movements of Huntington'sdisease.

As mentioned previously, magnesium ion is an NMDA receptor inhibitor,via blockade of calcium channels. I tested whether administration ofelemental magnesium would enhance the efficacy of acamprosate in thetreatment of simple tics. In Case 5, it is demonstrated thatsupplementing acamprosate with magnesium salts alleviates tics betterthan acamprosate alone. Therefore, magnesium may be combined with anyother agents that increase GABA transmission and/or decreaseNMDA-glutamate transmission to further suppress simple tics.

Both calcium acetylhomotaurinate and magnesium salts or chelates aresafe medications when given in appropriate dosage. Because magnesiumacetylhomotaurinate yields the same magnesium ions and homotaurinateions when it dissociates in the GI tract as does the mixture ofacamprosate and magnesium salts. I infer that magnesiumacetylhomotaurinate will also be a safe medication. Therefore, magnesiumN-acetylhomotaurinate would be a safe and effective drug, withpotentially greater efficacy for movement disorders than acamprosate(calcium), because of the NMDA-receptor blocking action of the magnesiumion. However, as noted earlier, it does not have the ideal molar ratioof magnesium to N-acetylhomotaurinate for maximal therapeutic effect.Therefore, a magnesium salt or chelate combined with a salt ofN-acetylhomotaurine or a derivative is likely to be more efficacious asa treatment for movement disorder. Magnesium ion combination withacamprosate and related compounds is likely to alleviate symptoms ofvarious hyperkinetic, dyskinetic, and dystonic movement disorders, forexample multiple tics, Tourette syndrome, tardive dyskinesia, andblepharospasm, and other focal dystonias.

It is likely that symptoms of the movement disorder associated withHuntington's disease will be relieved, at least in part, by acamprosate,alone or in combination with magnesium. Patients with Huntington'sdisease may show dyskinetic movements of the face and limbs resemblingthose of TD. Patients with Huntington's disease have a deficiency of GADin the striatum, and are thought to suffer from neuronal death due toNMDA-receptor mediated excitotoxicity (D E Riley and A E Lang: MovementDisorders, in W G Bradley et al., editors, Neurology in ClinicalPractice, Boston: Butterworth-Heinemann, 1991, p. 1568). These featuresof the disorder favor a positive response to acamprosate, a drug withjoint actions on GABA and NMDA-receptors.

One aspect of the method of the invention features improvements in thecognitive disorder associated with TD. The improvement in cognition andeveryday functional performance seen during the treatment of TD, makesacamprosate particularly attractive for patients with the cognitiveimpairment that frequently accompanies TD.

The relationship between tardive dyskinesia and cognitive impairment isnot fully understood. It is known that pre-existing cognitive impairmentincreases the risk that TD will develop in the event a patient receivesneuroleptics over a long-term period. It is also known that treatedschizophrenics with TD are more likely to show progressive cognitivedeterioration that those without TD. However, it is not known whethertreatment of TD will ameliorate the cognitive deficits associated withTD. Cases 1, 2, and 4 discussed above suggest that at least sometreatments of TD can ameliorate such cognitive deficits. The prior artdoes not report that the administration of acamprosate, when used as atreatment for alcoholism, improved the patients' cognition, I infer thatthe improvement in cognition seen in Cases 1, 2, and 4 was related tothe improvement in their movement disorders. This is consistent with thewell-established involvement of the basal ganglia in cognitive processes(Sano et al., Basal Ganglia Diseases, in Fogel et al., (eds.),Neuropsychiatry, Williams and Wilkins, 1996)

Moreover, the fact that acamprosate is also known as an agent used inthe treatment of alcoholism makes acamprosate particularly suited forthe treatment of patients who have a history of alcoholism in additionto a hyperkinetic movement disorder. Once such group is patients withschizophrenia and alcoholism (so called “dual diagnosis” patients) whohave TD, for which alcoholism is a risk factor.

Based on the foregoing, I claim the following:

1. A method for treating hyperkinesia comprising administering aneffective dose of acamprosate in an amount of about 1 g to about 2.6 gper day.
 2. The method of claim 1, wherein said step of administeringcomprises oral administration.
 3. A method of treating a hyperkineticmovement disorder comprising the step of administering an effective doseof acamprosate in an amount of about 1 g to about 2.6 g per day.
 4. Themethod of claim 3, wherein the hyperkinetic movement disorder is tardivedyskinesia or comprises involuntary movements similar to those seen insaid tardive dyskinesia.
 5. The method of claim 3, wherein said movementdisorder is the peak-dose dyskinesia in a patient with Parkinson'sdisease.
 6. The method of claim 3, wherein said movement disorder isassociated with Huntington's disease.
 7. The method of claim 3, whereinsaid movement disorder is related to a deficiency in GABA in the basalganglia.
 8. The method of claim 3, wherein said movement disorder isrelated to NMDA-based excitotoxicity.
 9. The method of claim 3comprising the further steps of: selecting an agent that is anoncompetitive antagonist at NMDA receptors; and administering saidagent in conjunction with said acamprosate.
 10. The method of claim 9,wherein said agent is memantine or a derivative thereof.
 11. The methodof claim 1, wherein the hyperkinesia comprises tardive dyskinesia.
 12. Amethod of treating tardive dyskinesia, comprising providing a patientsuffering from tardive dyskinesia with an effective dose of acamprosatein an amount of about 1 g to about 2.6 g per day.